New experiences are initially encoded as labile short-term memories, which are converted into stable long-term memory by gene transcription-dependent processes. In the hours after learning, the induction of gene expression follows a specific pattern that involves transient waves of transcriptional activity, which are needed for memory consolidation. Recent work has also identified persistent, long-lasting transcriptional changes that are induced by learning, which appear to contribute to storage of long-term memory. It is emerging that this transcription is regulated by epigenomic mechanisms such as histone acetylation and DNA methylation. These epigenetic modifications are critical for the long-lasting regulation of gene expression during development and may be a major mechanism of information storage in the brain. Changes in epigenetic modifications occur in animal models of depression and anxiety disorders, and alterations in DNA methylation have been found in post-mortem brains from patients with post-traumatic stress disorder, schizophrenia, autism and bipolar disorder. Defects in epigenetic modifications may contribute to impairments in synaptic plasticity and cognitive function associated with many psychiatric disorders. Our work suggests that epigenetic modifications are a critical component of both synaptic plasticity and memory formation and storage, but the genes targeted by these epigenetic regulatory processes remain unknown. In this application, we propose three Specific Aims to address these issues. In Specific Aim 1, we will examine the role of the NR4A orphan nuclear receptors, which are critical for long-term memory and long-term potentiation, as well as for the enhancement of memory and plasticity by HDAC inhibition. We will define the key NR4A target genes required for hippocampus-dependent memory and test if the NR4A transcription factors are novel targets for cognitive enhancement. In Specific Aim 2, we will define the molecular mechanisms through which the co-repressor SIN3A, which coordinates a transcriptional regulatory complex that includes histone-modifying enzymes HDAC1 and HDAC2, negatively regulates long-term memory and synaptic plasticity. Specific Aim 3 will build on evidence that a persistent long-lasting increase in the expression of transcription factor NFIL3 contributes to long-term memory storage in the hippocampus, thus defining the persistent transcription that mediates long-term memory storage in the hippocampus. Our understanding of the master transcriptional regulatory proteins involved in consolidation and storage of long- term memory may ultimately lead to the development of new treatments for the debilitating cognitive deficits associated with psychiatric disorders such as schizophrenia, bipolar disorder, post-traumatic stress disorder and depression.